A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

Silvia Moretti, Giorgia Renga, Vasilis Oikonomou, Claudia Galosi, Marilena Pariano, Rossana G Iannitti, Monica Borghi, Matteo Puccetti, Marco De Zuani, Carlo E Pucillo, Giuseppe Paolicelli, Teresa Zelante, Jean-Christophe Renauld, Oxana Bereshchenko, Paolo Sportoletti, Vincenzina Lucidi, Maria Chiara Russo, Carla Colombo, Ersilia Fiscarelli, Cornelia Lass-FlörlFabio Majo, Gabriella Ricciotti, Helmut Ellemunter, Luigi Ratclif, Vincenzo Nicola Talesa, Valerio Napolioni, Luigina Romani

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25+type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.

Original languageEnglish
Pages (from-to)14017
JournalNature Communications
Volume8
DOIs
Publication statusPublished - Jan 16 2017

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cystic fibrosis
Interleukin-9
interleukins
Cystic Fibrosis
Mast Cells
lungs
Pneumonia
Helper-Inducer T-Lymphocytes
Interleukin-2
Hypersensitivity
cells
Inflammation
Allergies
Lung
positive feedback
kits
Chemical activation
activation
Lymphocytes

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Moretti, S., Renga, G., Oikonomou, V., Galosi, C., Pariano, M., Iannitti, R. G., ... Romani, L. (2017). A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. Nature Communications, 8, 14017. https://doi.org/10.1038/ncomms14017

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. / Moretti, Silvia; Renga, Giorgia; Oikonomou, Vasilis; Galosi, Claudia; Pariano, Marilena; Iannitti, Rossana G; Borghi, Monica; Puccetti, Matteo; De Zuani, Marco; Pucillo, Carlo E; Paolicelli, Giuseppe; Zelante, Teresa; Renauld, Jean-Christophe; Bereshchenko, Oxana; Sportoletti, Paolo; Lucidi, Vincenzina; Russo, Maria Chiara; Colombo, Carla; Fiscarelli, Ersilia; Lass-Flörl, Cornelia; Majo, Fabio; Ricciotti, Gabriella; Ellemunter, Helmut; Ratclif, Luigi; Talesa, Vincenzo Nicola; Napolioni, Valerio; Romani, Luigina.

In: Nature Communications, Vol. 8, 16.01.2017, p. 14017.

Research output: Contribution to journalArticle

Moretti, S, Renga, G, Oikonomou, V, Galosi, C, Pariano, M, Iannitti, RG, Borghi, M, Puccetti, M, De Zuani, M, Pucillo, CE, Paolicelli, G, Zelante, T, Renauld, J-C, Bereshchenko, O, Sportoletti, P, Lucidi, V, Russo, MC, Colombo, C, Fiscarelli, E, Lass-Flörl, C, Majo, F, Ricciotti, G, Ellemunter, H, Ratclif, L, Talesa, VN, Napolioni, V & Romani, L 2017, 'A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis', Nature Communications, vol. 8, pp. 14017. https://doi.org/10.1038/ncomms14017
Moretti S, Renga G, Oikonomou V, Galosi C, Pariano M, Iannitti RG et al. A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. Nature Communications. 2017 Jan 16;8:14017. https://doi.org/10.1038/ncomms14017
Moretti, Silvia ; Renga, Giorgia ; Oikonomou, Vasilis ; Galosi, Claudia ; Pariano, Marilena ; Iannitti, Rossana G ; Borghi, Monica ; Puccetti, Matteo ; De Zuani, Marco ; Pucillo, Carlo E ; Paolicelli, Giuseppe ; Zelante, Teresa ; Renauld, Jean-Christophe ; Bereshchenko, Oxana ; Sportoletti, Paolo ; Lucidi, Vincenzina ; Russo, Maria Chiara ; Colombo, Carla ; Fiscarelli, Ersilia ; Lass-Flörl, Cornelia ; Majo, Fabio ; Ricciotti, Gabriella ; Ellemunter, Helmut ; Ratclif, Luigi ; Talesa, Vincenzo Nicola ; Napolioni, Valerio ; Romani, Luigina. / A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. In: Nature Communications. 2017 ; Vol. 8. pp. 14017.
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abstract = "T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25+type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.",
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